Clinical Trials Register

Summary
EudraCT Number:	2020-002761-33
Sponsor's Protocol Code Number:	R3918-PNH-2022
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2022-03-11
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2020-002761-33

A.3

Full title of the trial

A RANDOMIZED, OPEN-LABEL ECULIZUMAB AND RAVULIZUMAB CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF POZELIMAB AND CEMDISIRAN COMBINATION THERAPY IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA WHO ARE CURRENTLY TREATED WITH ECULIZUMAB OR RAVULIZUMAB

ESTUDIO ALEATORIZADO, ABIERTO Y CONTROLADO CON ECULIZUMAB Y RAVULIZUMAB PARA EVALUAR LA EFICACIA Y LA SEGURIDAD DEL TRATAMIENTO COMBINADO DE POZELIMAB Y CEMDISIRAN EN PACIENTES CON HEMOGLOBINURIA PAROXÍSTICA NOCTURNA TRATADOS ACTUALMENTE CON ECULIZUMAB O RAVULIZUMAB

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy and Safety of the Combination of Pozelimab and Cemdisiran versus continued Eculizumab or Ravulizumab Treatment in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria

ESTUDIO DE EFICACIA Y SEGURIDAD DEL TRATAMIENTO COMBINADO DE POZELIMAB Y CEMDISIRAN EN COMPARACIÓN AL TRATAMIENTO CONTINUADO CON ECULIZUMAB O RAVULIZUMA EN PACIENTES CON HEMOGLOBINURIA PAROXÍSTICA NOCTURNA.

A.4.1

Sponsor's protocol code number

R3918-PNH-2022

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Regeneron Pharmaceuticals, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Regeneron Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Regeneron Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	777 Old Saw Mill River Road
B.5.3.2	Town/ city	Tarrytown
B.5.3.3	Post code	10591
B.5.3.4	Country	United States
B.5.4	Telephone number	0034900 834223
B.5.6	E-mail	RegistroEspanolDeEstudiosClinicos@druginfo.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Pozelimab
D.3.2	Product code	REGN3918
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pozelimab
D.3.9.2	Current sponsor code	REGN3918
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cemdisiran
D.3.2	Product code	ALN-CC5
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CEMDISIRAN
D.3.9.2	Current sponsor code	ALN-CC5
D.3.9.3	Other descriptive name	CEMDISIRAN
D.3.9.4	EV Substance Code	SUB194793
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ULTOMIRIS ™ (ravulizumab-cwvz)
D.2.1.1.2	Name of the Marketing Authorisation holder	Alexion Pharmaceuticals, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ravulizumab
D.3.9.3	Other descriptive name	Ravulizumab
D.3.9.4	EV Substance Code	SUB192773
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Pozelimab
D.3.2	Product code	REGN3918
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pozelimab
D.3.9.2	Current sponsor code	REGN3918
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Soliris ™ (eculizumab)
D.2.1.1.2	Name of the Marketing Authorisation holder	Alexion Pharmaceuticals, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Eculizumab
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Eculizumab
D.3.9.1	CAS number	219685-50-4
D.3.9.4	EV Substance Code	SUB25187
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Paroxysmal nocturnal hemoglobinuria (PNH)

Hemoglobinuria paroxística nocturna (HPN)

E.1.1.1

Medical condition in easily understood language

A rare disease causing the breakdown of red blood cells.

Enfermedad Rara que causa la descomposición de los glóbulos rojos

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10055629
E.1.2	Term	Paroxysmal nocturnal hemoglobinuria
E.1.2	System Organ Class	100000004857

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

• To evaluate the effect of pozelimab and cemdisiran combination therapy on hemolysis, as assessed by LDH, after 36 weeks of treatment, in patients with PNH who switch from eculizumab or ravulizumab therapy versus patients who continue their eculizumab or ravulizumab therapy.

Evaluar el efecto sobre la hemólisis, determinado mediante la lactato deshidrogenasa (LDH), del tratamiento combinado con pozelimab y cemdisirán después de 36 semanas de tratamiento en pacientes con hemoglobinuria paroxística nocturna (HPN) que cambien a partir de eculizumab o ravulizumab en comparación con pacientes que continúen con el tratamiento con eculizumab o ravulizumab.

E.2.2

Secondary objectives of the trial

• Evaluate the effect of pozelimab and cemdisiran combination treatment versus anti-C5 standard-of-care treatment (eculizumab or ravulizumab) on the following:
− Transfusion requirements and transfusion parameters
− Measures of hemolysis: LDH control, breakthrough hemolysis, and inhibition of CH50
− Hemoglobin levels
− Fatigue as assessed by Clinical Outcome Assessments (COAs)
− HRQoL as assessed by COAs
− Safety and tolerability
• To assess the concentrations of total pozelimab and either total eculizumab or total ravulizumab in serum and total cemdisiran and total C5 protein in plasma
• To assess the immunogenicity of pozelimab and cemdisiran

•Evaluar el efecto del tratamiento combinado con pozelimab y cemdisirán, en comparación con el tratamiento de referencia anti-C5 (anticuerpos contra el factor 5 del complemento, ya sea eculizumab o ravulizumab), sobre lo siguiente:
-Necesidad de transfusiones y parámetros transfusionales.
-Medidas de la hemólisis: control de la LDH, hemólisis intercurrente e inhibición de la actividad hemolítica del complemento (CH50).
-Concentración de hemoglobina.
-Fatiga evaluada mediante evaluaciones de resultados clínicos (ERC).
-Calidad de vida relacionada con la salud (CVRS) evaluada mediante ERC.
-Seguridad y tolerabilidad.
•Determinar las concentraciones de pozelimab total y de eculizumab total o ravulizumab total en suero y de cemdisirán total y proteína C5 total en plasma.
•Evaluar la inmunogenicidad de pozelimab y cemdisirán.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Future Biomedical Research (Optional):
Patients who agree to participate in the future biomedical research (FBR) sub-study will be required to consent to this optional sub-study before samples are banked for FBR. Residual biomarker samples for study-related research, as well as unused PK and ADA samples, will be stored for up to 15 years after the final date of the database lock (or for a shorter time period if required per regional laws and regulations). The samples may be utilized for FBR that may or may
not be directly related to the study, including being used as reference samples and assay development or validation.

Pharmacogenomic Analysis (Optional):
Patients who agree to participate in the genomics sub-study will be required to consent to this optional sub-study before collection of the samples. Whole blood samples for DNA extraction should be collected on day 1/baseline (predose), but can be collected at a later study visit. Whole blood samples for RNA extraction will be collected at time points according to Table 1. DNA and RNA samples will be collected for pharmacogenomics analyses to understand the genetic
determinants of efficacy and safety associated with the treatments in this study and the molecular basis of PNH and related diseases. These samples will be single-coded as defined by the International Council on Harmonisation (ICH) guideline E15. Samples will be stored for up to 15 years after the final date of the database lock (or for a shorter time period if required per regional laws and regulations). If there are specific site or country requirements involving the
pharmacogenomic analyses which the sponsor is unable to comply with, samples will not be collected at those sites.
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or biomarker response to pozelimab and cemdisiran, other PNH clinical outcome measures and possible AEs. In addition, associations between genomic variants and prognosis or progression of PNH as well as related diseases may also be studied.
These data may be used or combined with data collected from other studies to identify and validate genomic markers related to the study
drug, target pathway, or PNH and related diseases.
Analyses may include sequence determination or single nucleotide polymorphism studies of candidate genes and surrounding genomic regions. Other methods, including whole-exome sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome
sequencing (or other methods for quantitating RNA expression) may also be performed. The list of methods may be expanded to include novel methodology that may be developed during the
course of this study or sample storage period.

Investigación biomédica futura (opcional):
Los pacientes que acepten participar en el futuro subestudio de investigación biomédica (FBR) deberán dar su consentimiento para este subestudio opcional antes de que las muestras se almacenen para FBR. Las muestras de biomarcadores residuales para la investigación relacionada con el estudio, así como las muestras PK y ADA no utilizadas, se almacenarán hasta 15 años después de la fecha final del bloqueo de la base de datos (o por un período de tiempo más corto si así lo requieren las leyes y regulaciones regionales). Las muestras se pueden utilizar para FBR que pueden o pueden no estar directamente relacionado con el estudio, incluido el uso como muestras de referencia y desarrollo o validación de ensayos.

Análisis Farmacogenómico (Opcional):
Los pacientes que acepten participar en el subestudio de genómica deberán dar su consentimiento para este subestudio opcional antes de la recolección de las muestras. Las muestras de sangre completa para la extracción de ADN se deben recolectar el día 1/basal (antes de la dosis), pero se pueden recolectar en una visita de estudio posterior. Las muestras de sangre completa para la extracción de ARN se recolectarán en puntos de tiempo de acuerdo con la Tabla 1. Las muestras de ADN y ARN se recolectarán para análisis de farmacogenómica para comprender la genética determinantes de eficacia y seguridad asociados con los tratamientos en este estudio y la base molecular de la PNH y enfermedades relacionadas. Estas muestras tendrán un código único según lo definido por la directriz E15 del Consejo Internacional de Armonización (ICH). Las muestras se almacenarán hasta 15 años después de la fecha final del bloqueo de la base de datos (o por un período de tiempo más corto si así lo requieren las leyes y regulaciones regionales). Si existen requisitos específicos del centro o del país que involucren la análisis farmacogenómicos que el patrocinador no pueda cumplir, no se tomarán muestras en esos centros.
El propósito de los análisis farmacogenómicos es identificar asociaciones genómicas con la respuesta clínica o de biomarcadores a pozelimab y cemdisiran, otras medidas de resultados clínicos de HPN y posibles eventos adversos. Además, también se pueden estudiar las asociaciones entre las variantes genómicas y el pronóstico o la progresión de la PNH, así como las enfermedades relacionadas.
Estos datos pueden usarse o combinarse con datos recopilados de otros estudios para identificar y validar marcadores genómicos relacionados con el estudio, fármaco, vía diana o PNH y enfermedades relacionadas.
Los análisis pueden incluir la determinación de secuencias o estudios de polimorfismos de un solo nucleótido de genes candidatos y regiones genómicas circundantes. Otros métodos, incluida la secuenciación del exoma completo, la secuenciación del genoma completo, la variación del número de copias de ADN y el transcriptoma también se puede realizar la secuenciación (u otros métodos para cuantificar la expresión de ARN). La lista de métodos puede ampliarse para incluir metodologías novedosas que pueden desarrollarse durante el curso de este estudio o período de almacenamiento de la muestra.

E.3

Principal inclusion criteria

1. Diagnosis of PNH confirmed by a history of high-sensitivity flow cytometry from prior testing
2. Treated with eculizumab or ravulizumab prior to screening visit as described in the protocol Note: Biosimilars are not permitted, unless approved by the Sponsor

Note: Other protocol-defined Inclusion Criteria apply

1. Diagnóstico de HPN confirmado por una citometría de flujo de alta sensibilidad en pruebas previas.
2. Tratamiento con eculizumab or ravulizumab antes de la visita de selección como se describe en el protocolo. Nota: No se permite el uso de biosimilares, a menos que lo apruebe el promotor.

Nota: Aplican los otros Criterios de Inclusión definidos en el protocolo

E.4

Principal exclusion criteria

1. Patients with a screening LDH >1.5 × ULN who have not taken their C5 inhibitor within the labeled dose interval at the dose prior to the screening LDH assessment
2. Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant
3. Body weight < 40 kilograms at screening visit
4. Any use of complement inhibitor therapy other than eculizumab or ravulizumab in the 26 weeks prior to the screening visit or planned use during the study with the exception of study treatments
5. Not meeting meningococcal vaccination requirements for eculizumab or ravulizumab according to the current local prescribing information (where available) and at a minimum documentation of meningococcal vaccination within 5 years prior to screening visit.
6. Any contraindication for receiving Neisseria meningitidis vaccination.
7. Positive for hepatitis B, and/ or hepatitis C as described in the protocol
8. History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer
9. Participation in another interventional clinical study (except R3918-PNH-2021) or use of any experimental therapy within 30 days before screening visit or within 5 half-lives of that investigational product, whichever is greater, with the exception of eculizumab or ravulizumab.
10. Patients with functional or anatomic asplenia

Note: Other protocol-defined Exclusion Criteria apply

1.Pacientes con una LDH en la selección > 1,5 veces el LSN que no hayan recibido su inhibidor de C5 dentro del intervalo de dosis autorizado en la dosis previa a la evaluación de la LDH en la selección.
2.Recepción de un trasplante de órgano, antecedentes de trasplante de médula ósea u otro trasplante hematológico.
3.Peso corporal < 40 kg en la visita de selección.
4. Cualquier uso de tratamiento con inhibidores del complemento distintos de eculizumab o ravulizumab en las 26 semanas previas a la visita de selección o uso previsto durante el estudio, con la excepción de los tratamientos del estudio.
5.Incumplimiento de los requisitos de vacunación antimeningocócica para eculizumab o ravulizumab de conformidad con la ficha técnica local vigente (cuando esté disponible) y con una documentación mínima de la vacunación antimeningocócica en los 5 años previos a la visita de selección.
6.Cualquier contraindicación para recibir la vacuna contra Neisseria meningitidis.
7.Positividad del antígeno de superficie del virus de la hepatitis B o del ARN del virus de la hepatitis C como se describe en el protocolo.
8.Antecedentes de cáncer en los últimos 5 años, excepto carcinoma basocelular de piel, carcinoma espinocelular de piel o cáncer de cuello uterino in situ debidamente tratados.
9.Participación en otro estudio clínico intervencionista (excepto R3918-PNH-2021) o uso de cualquier tratamiento experimental en los 30 días previos a la visita de selección o en el periodo equivalente a 5 semividas de dicho producto en investigación, lo que suponga más tiempo, con la excepción de eculizumab o ravulizumab.
10. Pacientes con asplenia funcional o anatómica.

Nota: Nota: Aplican los otros Criterios de Exclusión definidos en el protocolo

E.5 End points

E.5.1

Primary end point(s)

Percent change in lactate dehydrogenase (LDH)

Variación porcentual de la Lactato Deshidrogenasa (LDH )

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline to week 36

Desde el momento basa a la semana 36

E.5.2

Secondary end point(s)

1. Proportion of patients with transfusion avoidance
2. Proportion of patients with transfusion avoidance
3. Proportion of patients with breakthrough hemolysis
4. Proportion of patients with breakthrough hemolysis
5. Proportion of patients with hemoglobin stabilization
6. Proportion of patients with hemoglobin stabilization
7. Proportion of patients with adequate control of LDH
8. Proportion of patients with adequate control of LDH
9. Proportion of patients with normalization of LDH
10. Proportion of patients with normalization of LDH
11. Change in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale
12. Change in Physical Function (PF) score on the European organization for research and treatment of cancer quality-of-Life questionnaire Core 30 Items (EORTC-QLQ-C30)
13. Change in global health status (GHS)/QoL scale score on the EORTC-QLQ-C30
14. Rate of RBCs transfused per protocol algorithm
15. Rate of RBCs transfused per protocol algorithm
16. Number of units of RBCs transfused per protocol algorithm
17. Number of units of RBCs transfused per protocol algorithm
18. Change in hemoglobin levels
19. Incidence and severity of treatment emergent serious adverse events (SAEs)
20. Incidence and severity of treatment-emergent adverse events (TEAEs) of special interest
21. Incidence and severity TEAEs leading to treatment discontinuation
22. Change in total CH50
23. Percent change in total CH50
24. Concentration of total C5 in plasma
25. Concentrations of total pozelimab in serum
26. Concentrations of total cemdisiran in plasma
27. Concentrations of total eculizumab
28. Concentrations of total ravulizumab in serum
29. Incidence of treatment emergent anti-drug antibodies (ADAs) to pozelimab
30. Incidence of treatment emergent ADAs to cemdisiran

1.Proporción de pacientes que evitan las transfusiones
2.Proporción de pacientes que evitan las transfusiones
3.Proporción de pacientes con hemólisis intercurrente
4.Proporción de pacientes con hemólisis intercurrente
5.Proporción de pacientes con estabilización de la hemoglobina
6.Proporción de pacientes con estabilización de la hemoglobina
7.Proporción de pacientes con un control adecuado de la LDH
8.Proporción de pacientes con un control adecuado de la LDH
9.Proporción de pacientes con un control adecuado de la LDH
10.Proporción de pacientes con un control adecuado de la LDH
11. Variación de la fatiga medida mediante la escala de fatiga de la valoración funcional del tratamiento de enfermedades crónicas (FACIT-Fatiga).
12.Variación de la puntuación de función física (FF) en el cuestionario EORTC QLQ-C30 (Cuestionario de calidad de vida-Módulo básico de 30
apartados de la Organización Europea para la Investigación y el Tratamiento del Cáncer)
13.Variación de la puntuación de la escala de estado general de salud/CdV del cuestionario EORTC-QLQ-C30
14.Tasa de eritrocitos transfundidos según el algoritmo
15.Tasa de eritrocitos transfundidos según el algoritmo
16.Número de unidades de eritrocitos transfundidos según el algoritmo
17.Número de unidades de eritrocitos transfundidos según el algoritmo
18.Variación de la concentración de hemoglobina
19.Incidencia e intensidad de los acontecimientos adversos graves (AAG)
20.Incidencia e intensidad de los acontecimientos adversos surgidos durante el tratamiento (AAST) de interés especial
21.Incidencia e intensidad de los acontecimientos adversos surgidos durante el tratamiento (AAST) que motiven la suspensión del tratamiento
22.Variación total del complemento (CH50)
23.Variación porcentual del complemento (CH50)
24.Concentración plasmática de C5
25.Concentración sérica de pozelimab total
26. Concentración plasmática de cemdisirán total
27. Concentración de eculizumab total
28. Concentración sérica de ravulizumab total
29. Incidencia de anticuerpos contra el fármaco (ACF) antipozelimab
30. Incidencia de ACF anticemdisirán

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Day 1 through week 36
2. Week 4 through week 36
3. Day 1 through week 36
4. Week 4 (day 29) through week 36
5. Day 1 through week 36
6. Week 4 (day 29) through week 36
7. Day 1 through week 36
8. Week 8 (day 57) through week 36
9. Day 1 through week 36
10. Week 8 (day 57) through week 36
11-13. From baseline to week 36
14. Day 1 through week 36
15. Week 4 through week 36
16. Day 1 through week 36
17. Week 4 through week 36
18. From baseline to week 36
19-21. Up to 88 weeks
22-23. From baseline to week 36
24-25. Through week 62
26. Through week 32
27. Through week 40
28. Through week 44
29-30. Through week 62

1.Desde día 1 hasta semana 36
2.Desde semana 4 hasta semana 36
3.Desde día 1 hasta semana 36
4.Desde semana 4 (día 29) hasta semana 36
5.Desde día 1 hasta semana 36
6.Desde semana 4 (día 29) hasta semana 36
7.Desde día 1 hasta semana 36
8.Desde semana 8 (día 57) hasta semana 36
9.Desde semana 8 (día 57) hasta semana 36
10. Desde semana 8 (día 57) hasta semana 36
11-13.Desde momento basal a la semana 36
14. Desde día 1 hasta semana 36
15. Desde semana 4 hasta semana 36
16. Desde día 1 hasta semana 36
17. Desde semana 4 hasta semana 36
18. Desde momento basal a la semana 36
19-21. Durante 88 semanas
22-23.Desde momento basal a semana 36
24-25.Hasta semana 62
26.Hasta semana 32
27.Hasta semana 40
28.Hasta semana 44
29-30.Hasta semana 62

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Brazil

Colombia

Japan

Korea, Republic of

Mexico

Philippines

Singapore

Taiwan

Turkey

United States

France

Germany

Greece

Italy

Netherlands

Poland

Portugal

Romania

Spain

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

Última visita último paciente

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

112

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

140

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients who complete the OLTP will be offered the opportunity to enroll in another study, a follow-on OLE study. For patients who complete the 36-week OLTP on the pozelimab and cemdisiran arm, the transition of treatment from the current study to the OLE is planned to be uninterrupted. Patients who complete the 36-week OLTP on the anti-C5 standard-of-care arm will undergo a transition period in order to switch to cemdisiran and pozelimab combination treatment

Se ofrecerá participar en el estudio de extensión abierto a largo plazo del tratamiento combinado a todos los pacientes que completen el estudio.
Los pacientes aleatorizados al grupo de tratamiento de referencia anti-C5 que completen el periodo de tratamiento abierto de 36 semanas y tengan previsto incorporarse al estudio de extensión abierto deberán pasar un periodo de transición

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-05-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-05-06

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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